CN108175442A - A kind of acoustic contrast agent method for measuring non-linear parameters - Google Patents

Abstract

The present invention relates to a kind of acoustic contrast agent method for measuring non-linear parameters.The principle of the invention：After acoustic contrast agent microvesicle being added in aqueous medium, the presence of microbubble changes the physical characteristic of aqueous medium, so as to cause the significant change of sound pressure amplitude is measured, and then lead to the change of nonlinear parameter, so the situation of change of nonlinear parameter can be extrapolated by measuring the variation of acoustic pressure amplitude.The measuring method of the present invention is suitable for the measurement of a variety of acoustic contrast agent nonlinear parameters, measures more convenient, and repeatability is strong, and data are easily obtained and handled, and can not only measure second nonlinear parameter, can also measure three ranks and high-order nonlinear parameter.

Description

A Method for Measuring the Nonlinear Parameters of Ultrasound Contrast Agent

technical field

The invention belongs to the combination of ultrasonic medical treatment and acoustic technology fields, and in particular relates to a method for measuring nonlinear parameters of an ultrasonic contrast agent.

Background technique

In recent years, in the field of clinical medical ultrasound diagnosis and biological tissue imaging, microbubble ultrasound contrast agents have received more and more attention, and ultrasound technology has also been applied to various treatment equipment. A large number of research results at home and abroad have shown that using The non-linear vibration and scattering characteristics generated when the microbubbles are excited by sound waves can improve the efficiency of ultrasound therapy and implement intravascular thrombolysis, and carry therapeutic drugs or genes through micronanobubbles, and use ultrasound as a mediated method to carry out anti-inflammatory effects. Targeted delivery of tumor drugs, targeted transfection or delivery of genes, etc. Therefore, the combination of microbubbles and ultrasound for the treatment of some major diseases has become one of the hot spots of domestic and foreign medical circles.

When the sound wave propagates in the medium, the forced vibration of the bubble will cause the sound scattering, reflecting the strong nonlinear acoustic characteristics. The nonlinear effect of the medium is generally characterized by the nonlinear parameter B/A, which reflects the dynamic characteristics of the medium. At the same time, the third-order nonlinear parameter C/A can also reflect the dynamic characteristics of the material and the change of the material structure, and can also be considered as an important parameter of medium properties. Therefore, effective measurement of nonlinear parameters is the key to the study of ultrasound medicine. In view of the fact that the existing finite amplitude method is only suitable for near-field measurement, a measurement method that can avoid the instability caused by the fluctuation of sound pressure amplitude in near-field measurement and reduce the distance detection error is proposed: using limited After amplitude comparison method and correction of acoustic wave attenuation coefficient, the nonlinear parameters of deaerated water and microbubble water medium containing ultrasonic contrast agent under the action of fundamental wave and multiple harmonics were measured. The measurement principle is: after adding ultrasonic contrast agent microbubbles in the water medium, the existence of the microbubbles changes the physical properties of the water medium, which leads to a significant change in the measured sound pressure amplitude, which in turn leads to a change in nonlinear parameters. The variation of the nonlinear parameter is deduced by measuring the variation of the sound pressure amplitude, therefore, the present invention provides an effective measurement method based on such a principle.

Contents of the invention

Aiming at the deficiencies of the prior art, the invention provides a method for measuring the nonlinear parameters of the ultrasound contrast agent.

Technical solution of the present invention is:

Compared with degassed water, the acoustic properties of aqueous media containing ultrasound contrast agents are significantly different, mainly because when sound waves propagate in media containing ultrasound contrast agents, the vibration of bubble groups will cause strong sound scattering, especially in the When the bubble resonates, this kind of scattering is manifested as a strong nonlinear characteristic, so that not only the fundamental wave propagates in the medium, but also the higher harmonic exists. As the most obvious high-order wave, the research on the second-order nonlinear harmonic has made a lot of progress, and previous scholars have done a lot of work in experiments. However, the development of medical ultrasound has put forward new requirements for the research of higher-order harmonics. Therefore, the present invention further studies the generation of third-order nonlinear harmonics in the medium containing microbubbles, and the purpose is to obtain third-order nonlinear harmonics. The calculation method of the parameter.

Although many acoustic studies are based on linear acoustic theory, in fact, acoustics is basically nonlinear. Under the conditions of isentropy or adiabatic, the equation of state p=p(ρ,s) can be expanded into the following Taylor level The number form is:

The second-order nonlinear parameters are defined as:

Similarly, the third-order nonlinear parameters are defined as:

Among them, p, ρ and c are the pressure, density and sound velocity of the medium, p ₀ , ρ ₀ and c ₀ represent the amount of the medium without disturbance, and s is the entropy. For a given medium, B/A and C/A are constants, but due to the existence of nonlinearity in the medium, when the finite-amplitude sound wave propagates in the medium, harmonics will be generated due to waveform distortion, resulting in a sound wave in the propagation process. attenuation. Assuming that the attenuation of the fundamental and higher harmonics is independent of each other, the change in the amplitude of the second and third harmonics can be expressed as the sum of the changes caused by harmonic generation and absorption attenuation. Since the attenuation of the ultrasonic wave in the medium will cause the actual measured amplitude to be smaller than the theoretical value, so in order to improve the measurement accuracy, the loss of the medium should be considered in the calculation and the sound propagation attenuation should be corrected, then the distance sound can be obtained The magnitude of the second harmonic sound pressure at source x is

Then the second-order nonlinear parameter becomes

Similarly, the third harmonic sound pressure amplitude is

Then the third-order nonlinear parameter becomes

Among them, ρ ₀ and c ₀ respectively represent the density and sound velocity of the medium, x is the distance of propagation, f is the frequency of the emission source, p ₀ is the amplitude of the sound wave emission source, α ₁ , α ₂ , and α ₃ are the fundamental wave and the secondary wave respectively The attenuation coefficient of harmonic and third harmonic and in biological media, the sound attenuation coefficient is proportional to the frequency.

Obtaining accurate attenuation coefficients is a prerequisite for attenuation correction. Therefore, it is necessary to carry out measurement and research on the attenuation coefficients of the fundamental, second and third harmonics, which can be calculated by the following amplitude comparison method. It is known that the attenuation law of sound wave with distance is p ₁₀ =p ₀ e ^-αx , after adding microbubbles, the sound pressure becomes , where p ₀ is the sound wave amplitude at the transmitting end, p ₁₀ and p _1x are the sound wave amplitudes at the distance x from the sound wave after adding microbubbles to the water medium, respectively; α is the attenuation coefficient at the known water temperature and ultrasonic frequency. Comparing the left and right sides of the above two formulas, taking the natural logarithm, the fundamental wave attenuation coefficient after adding microbubbles is

In actual measurement, what is measured is the voltage amplitude at the receiving transducer end, because the voltage value at the receiving end can be expressed linearly by the sound pressure value and the sensitivity μ of the receiving transducer

Then formula (9) becomes

Among them, V ₁₀ and V _1x are the receiving end voltage amplitudes in degassed water and medium containing microbubbles, which can be directly measured through experiments, and combined with the known temperature and the attenuation coefficient of water medium at ultrasonic frequency, the medium containing microbubbles can be obtained attenuation coefficient. Similarly, the attenuation coefficients of the second and third harmonics can be calculated.

In a mixed medium, if the mixed liquid with ultrasonic contrast agent microbubbles is close to the acoustic characteristics of the liquid medium, the sound pressure amplitude satisfies:

Comparing the left and right sides of the two expressions in the equation system,

In the same way,

Comparing the left and right sides of the two expressions in the equation system,

The subscripts "0" and "x" denote the physical quantities of degassed water and the medium to be measured (ultrasound contrast agent), respectively. Both ρ ₀ and c ₀ of the reference medium are known, and ρ _x and c _x of the medium to be measured are also known. Determination, α ₁ , α ₂ , α ₃ are the attenuation coefficients of the fundamental wave, the second and the third harmonic respectively, which can be calculated by formula (10). Bringing these parameters into (12) and (14) formulas can calculate the nonlinear parameters of the medium to be measured (ultrasound contrast agent).

The experimental device of the measurement method of the present invention mainly includes: a signal generator, a power amplifier, a transducer, a high-precision three-dimensional ultrasonic scanning control mechanism, a hydrophone, a digital oscilloscope, a program-controlled computer, and the like. Among them, the planar transducer is fixed at one end of the water tank, which avoids that when the transducer and the hydrophone are moved at the same time, it is difficult for the sound axes of the two to reach a coaxial state. The hydrophone is installed on a high-precision three-dimensional ultrasonic scanning control mechanism, and the program-controlled computer controls the movement of the hydrophone to collect acoustic signals at different distances. The hydrophone is connected to the digital oscilloscope as the sound wave receiving end, the trigger signal of the signal generator is connected to the digital oscilloscope as the synchronous signal end, and the program-controlled computer is connected to the digital oscilloscope to read and store the signal.

Furthermore, the signal generator used is a Puyuan Precision Electronics DG4062 signal generator capable of simultaneously sending dual-channel signals, which meets the experimental requirements.

Furthermore, the transducer used is a planar piston transducer with a diameter of 30 mm and a resonant frequency of 2.3 MHz.

Furthermore, the hydrophone used is a thin-film hydrophone with a diameter of 100 mm and a very good frequency response in common ultrasonic medical treatment.

Furthermore, the amplifier used is RITEC's RPR-4000 power amplifier, with a maximum power output of 8KW, which meets the experimental requirements.

Furthermore, the motion control part adopts a high-precision three-dimensional ultrasonic scanning control mechanism, and a program-controlled computer controls the motion of the hydrophone.

Furthermore, the oscilloscope mentioned is the DS2102 dual-channel oscilloscope of Puyuan Precision Electronics.

Furthermore, the water tank is a small water tank customized with acrylic board, and the size of the water tank is designed after calculating the near and far field distances.

Beneficial effects of the present invention: since the price of ultrasound contrast agent is generally expensive, the experimental area is selected in a small water tank customized by acrylic plate. The concentration of the agent is not too low, avoiding the waste of ultrasonic contrast agent, and also ensuring that the thin film hydrophone can move in the water tank, improving the accuracy of averaging multiple measurements of nonlinear parameters, and avoiding the measurement of non-linear parameters in a single position. In addition, there is a small hole at one end of the water tank to fix the transducer, which avoids the fact that it is difficult to achieve a coaxial state when the transducer and the hydrophone are moved at the same time. The hydrophone is installed on the high-precision three-dimensional ultrasonic scanning control mechanism, and the program-controlled computer controls the movement of the hydrophone to collect sound wave signals at different distances, avoiding the measurement error caused by the instability of near-field sound pressure, and the measurement of the present invention The method is suitable for the measurement of nonlinear parameters of various ultrasound contrast agents. It is convenient to measure, has strong repeatability, and is easy to obtain and process data. It can not only measure second-order nonlinear parameters, but also third-order and higher-order nonlinear parameters.

Description of drawings

Fig. 1 is a schematic diagram of the measuring device of the present invention.

Fig. 2 Sensitivity curve of membrane hydrophone.

Figure 3 Schematic diagram of output pulse signal transient steady state.

In the figure: 1. Signal generator, 2. Power amplifier, 3. Planar piston transducer, 4. Program-controlled computer, 5. High-precision three-dimensional ultrasonic scanning control mechanism, 6. Thin-film hydrophone, 7. Digital oscilloscope, 8 , (ultrasound contrast agent) medium, 9, radiation sound field.

Detailed ways

Below in conjunction with accompanying drawing, the present invention will be further described:

As shown in Figure 1, the burst sinusoidal pulse signal that signal generator 1 produces is connected as the external trigger of digital oscilloscope 7 as synchronous signal, is used for capturing sound pressure waveform and calculating planar piston transducer 3 and membrane hydrophone 6 (sensitivity The curve is very gentle, the frequency response is good, as shown in Figure 2), and at the same time, the 20-period continuous signal with a center frequency of 3MHz generated by the signal generator 1 passes through the power amplifier 2 (frequency range 0.5MHz to 45MHz , gain 50dB) to excite the planar piston transducer 3 (center frequency is 2.3MHz, diameter is 30mm) to emit sound waves, forming a radiation sound field 9 in the water tank, and the thin film hydrophone 6 is used as a receiving device to convert the received sound signal into an electrical signal , displayed on the digital oscilloscope 7. The thin-film hydrophone 6 is installed on the high-precision three-dimensional ultrasonic scanning control mechanism 5, and the movement of the thin-film hydrophone 6 is controlled by the program-controlled computer 4.

At the beginning, move the thin film hydrophone 6 close to the planar piston transducer 3 and move it to the near field (try to ensure the common acoustic axis of the transducer and the hydrophone to increase the receiving sensitivity of the system and improve the ability to receive weak signals) , and then slowly move away from the planar piston transducer 3 to measure acoustic signals at different distances. The signal is read and stored through the LABVIEW program serial port in the program-controlled computer 4, and then the signal amplitude is obtained by extracting the signal and Fourier transform, and then the nonlinear parameter values of different distances can be calculated, and finally can be obtained Mean values of nonlinear parameters in microbubble media containing ultrasound contrast agents.

(1) Signal excitation part

During the experiment, it is necessary to provide the oscilloscope with a trigger signal synchronized with the transmitted signal to capture the sound pressure waveform and calculate the time delay between the transmitted wave and the received wave, so the signal generator selected is the DG1022U dual-channel of Puyuan Precision Electronics. Signal generator, it has the function of dual channels that can send signals at the same time, which meets the requirements of the experiment. However, the excitation voltage amplitude of the signal generator is limited, which is not enough to excite the transducer to generate nonlinear signals, so it needs to be amplified. RITEC's RPR-4000 signal power amplifier is used in the experiment. It has functions such as self-sending and self-receiving, threshold excitation, and leakage protection. The maximum power output reaches 8KW, which meets the experimental requirements.

When the transducer is working, the vibration of the crystal element will cause friction and heat generation. When the transducer works for a long time under the excitation of high-power continuous signal, it is easy to generate heat and cause damage. Moreover, due to the limited experimental space, reverberation field is easy to be generated when the continuous signal is excited. Affects the extraction of useful signals. Therefore, in order to protect the transducer while avoiding the reverberation field, the excitation signal generally adopts a burst sinusoidal pulse signal, which has both the nature of a pulse signal and a stable state, and can complete data acquisition before the arrival of the reflected signal to avoid the formation of a reverberation field.

(2) Data acquisition part

The data acquisition part includes two parts, a digital oscilloscope and a program-controlled computer. The digital oscilloscope is the DS2102 dual-channel oscilloscope of Puyuan Precision Electronics. It has waveform triggering, memory reading, and storage functions. The real-time sampling rate can reach 2GSa/s, the bandwidth can reach 200MHz, and it has serial communication. Realize the parameter setting, status query and reading data of the oscilloscope. To meet the experimental needs, the digital oscilloscope is used as a relay component to transmit the signal received by the membrane hydrophone to the program-controlled computer for display and storage on the computer.

When the sinusoidal pulse excites the transducer, the transducer is driven, and it takes a period of time to reach a stable working state at the beginning. When the excitation signal ends, the transducer still needs to damp vibration for a period of time. Therefore, there will be transient phenomena at the front and tail of the output pulse signal, as shown in FIG. 3 . Parameters such as effective sound pressure and sound operating frequency are defined according to the steady-state working state of the transducer, so the transient part of the signal is not available and the width of the excitation pulse cannot be smaller than the transient process. According to the actual situation, the experiment gave 20 periodic signals, when collecting signals, generally read several periodic signals of the steady state part (to reduce the instability of the measurement signal), and then obtain the sound pressure signal by processing the waveform, and then calculate the nonlinear parameter value.

(3) Motion control part

The motion control part in the experiment is mainly controlled by the LABVIEW program in the computer to control the movement of the stepper motor in the high-precision three-dimensional scanning motion control mechanism. As the executive mechanism of the movement, the stepping motor receives the pulse signal sent by the computer and converts the received electric pulse into its own angular displacement, thereby driving the membrane hydrophone to move in the tank and completing the signal collection of each point. It not only avoids the instability caused by the near-field sound pressure fluctuation, but also greatly reduces the occasional error formed when measuring the nonlinear parameter of a single position.

In summary, the measuring method of the present invention is suitable for measuring different types of ultrasound contrast agents. The size of the water tank is designed after calculating the near and far field distance, which ensures that the concentration of the ultrasound contrast agent will not be too low, reduces the diffusion of the ultrasound contrast agent to the outside of the experimental area, and makes it fully play its role in the experimental measurement area. It avoids the waste of ultrasonic contrast agent, and at the same time ensures that the thin film hydrophone can move in the tank, and improves the accuracy of averaging multiple measurements of nonlinear parameters. It can not only measure second-order nonlinear parameters, but also measure third-order nonlinear parameters. first-order and higher-order nonlinear parameters. The proposal of this measurement method will help to improve the contrast effect of ultrasound contrast agents through accurate measurement of nonlinear parameters and provide more effective scientific basis for clinical ultrasound diagnosis and treatment.

Claims (1)

1. A method for measuring nonlinear parameters of ultrasound contrast agents, characterized in that: Under isentropic or adiabatic conditions, the equation of state p=p(ρ,s) is expanded into the following Taylor series form: The second-order nonlinear parameters are defined as: The third-order nonlinear parameters are defined as: Among them, p, ρ and c are the pressure, density and sound velocity of the medium respectively, p ₀ , ρ ₀ and c ₀ represent the amount of the medium without disturbance, s is the entropy; for a given medium, B/A and C/A is a constant; assuming that the attenuation of the fundamental wave and higher harmonics is independent of each other, the change of the second and third harmonic amplitudes can be expressed as the sum of the changes caused by harmonic generation and absorption attenuation; due to the attenuation of ultrasonic waves in the medium The actual measured amplitude will be smaller than the theoretical value. In order to improve the measurement accuracy, the loss of the medium and the sound propagation attenuation must be considered in the calculation, and the second harmonic sound pressure amplitude at the distance x from the sound source can be obtained value is Then the second-order nonlinear parameter becomes The amplitude of the third harmonic sound pressure is Then the third-order nonlinear parameter becomes Where x is the propagation distance, f is the source frequency, p ₀ is the amplitude of the source, α ₁ , α ₂ , α ₃ are the attenuation coefficients of the fundamental wave, the second harmonic and the third harmonic respectively, and in biological In the medium, the sound attenuation coefficient is proportional to the frequency; It is known that the attenuation law of sound wave with distance is p ₁₀ =p ₀ e ^-αx , after adding microbubbles, the sound pressure becomes Among them, p ₀ is the sound wave amplitude of the transmitting end, p ₁₀ and p _1x are the sound wave amplitudes of the water medium and the distance x from the transmitting end after adding microbubbles; α is the attenuation coefficient at the known water temperature and ultrasonic frequency; Comparing the left and right sides of the above two formulas, taking the natural logarithm, the fundamental wave attenuation coefficient after adding microbubbles is In actual measurement, what is measured is the voltage amplitude at the receiving transducer end, and the voltage value at the receiving end can be linearly expressed by the sound pressure value and the sensitivity μ of the receiving transducer Then formula (9) becomes Among them, V ₁₀ and V _1x are the voltage amplitudes at the distance x from the receiving end to the transmitting end in degassed water and medium containing microbubbles, which can be measured directly, combined with the known temperature and the attenuation coefficient of the water medium at ultrasonic frequencies. Obtain the attenuation coefficient of the medium containing microbubbles; similarly, the attenuation coefficient of the second and third harmonics can be calculated; In a mixed medium, if the mixed liquid with ultrasonic contrast agent microbubbles is close to the acoustic characteristics of the liquid medium, the sound pressure amplitude satisfies: Comparing the left and right sides of the two expressions in the equation system, In the same way, Comparing the left and right sides of the two expressions in the equation system, The subscripts "0" and "x" denote the physical quantities of the deaerated water and the medium to be measured, respectively. For the reference medium, ρ ₀ and c ₀ are known, and for the medium to be measured, ρ _x and c _x are also easy to measure, α ₁ , α ₂ , and α ₃ can be calculated by formula (10); bringing these parameters into formulas (12) and (14) can calculate the nonlinear parameters of the medium to be measured, that is, the nonlinear parameters of the ultrasound contrast agent.